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Clinical Use of Dexmedetomidine Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western.

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Presentation on theme: "Clinical Use of Dexmedetomidine Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western."— Presentation transcript:

1 Clinical Use of Dexmedetomidine Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio, USA October 7, 2003

2 Objectives Pharmacology of dexPharmacology of dex –alpha 2 agonist Molecular targets + neural substratesMolecular targets + neural substrates –locus caeruleus –natural sleep pathways Clinical paradigms for use of dex in anesthesiaClinical paradigms for use of dex in anesthesia –sedation + analgesia w/o resp depression –attenuation of tachycardia –smooth emergence + weaning from mech vent

3 Pharmacology Establish and maintain adequate drug concentration at effector site to produce desired effectEstablish and maintain adequate drug concentration at effector site to produce desired effect –sedation –hypnosis –analgesia –paralysis Predict the time course of drug onset + offsetPredict the time course of drug onset + offset

4 Pharmacodynamics Relationship between drug conc + effectRelationship between drug conc + effect Interaction of drug with receptorInteraction of drug with receptor ReceptorReceptor –cell component –interacts with drug –biochemical change Examples of receptors:Examples of receptors: –AchR, GABA, opioid,  +  adrenergic

5 Receptors Coupled to ion channelsCoupled to ion channels –neural signaling, 2nd messenger effects Drug effects at receptorDrug effects at receptor –agonist, antagonist or mixed effects –stereospecificity, racemic mixture of isomers Receptor alterationsReceptor alterations –upregulated or downregulated (e.g., CHF) –  or  number (e.g., burns, myasthenia gravis)

6 Pharmacodynamics Sedation/hypnosisSedation/hypnosis AnxiolysisAnxiolysis AnalgesiaAnalgesia Sympatholysis (BP/HR, NE)Sympatholysis (BP/HR, NE) Reduces shiveringReduces shivering Neuroprotective effectsNeuroprotective effects No effect on ICPNo effect on ICP No respiratory depressionNo respiratory depression

7 Pharmacokinetics Rapid redistribution: 6 minRapid redistribution: 6 min Elimination half-life: 2 hElimination half-life: 2 h Vd steady state: 118 LVd steady state: 118 L Clearance: 39 L/hClearance: 39 L/h Protein binding: 94%Protein binding: 94% Metabolism: biotransformation in liver to inactive metabolites + excreted in urineMetabolism: biotransformation in liver to inactive metabolites + excreted in urine No accumulation after infusions hNo accumulation after infusions h Pharmacokinetics similar in young adults + elderlyPharmacokinetics similar in young adults + elderly

8  2 Agonists Clonidine Selectivity:  2 :  1 200:1Selectivity:  2 :  1 200:1 t 1/2  8 hrs 1t 1/2  8 hrs 1 PO, patch, epiduralPO, patch, epidural AntihypertensiveAntihypertensive Analgesic adjunctAnalgesic adjunct IV formulation not available in USIV formulation not available in US Dexmedetomidine Selectivity:  2 :  :1 t 1/2  2 hrs Intravenous Sedative-analgesic Primary sedative Only IV  2 available for use in the US

9 Mechanism for the Hypnotic Effect Hyperpolarization of locus ceruleus neuronsHyperpolarization of locus ceruleus neurons –  2A -Adrenoreceptor subtype –Activation of K + channels –Inhibition of Ca ++ channels –Inhibition of adenylyl cyclase  Firing rate of locus caeruleus neurons  Firing rate of locus caeruleus neurons  Activity in ascending noradrenergic pathway  Activity in ascending noradrenergic pathway

10 Restorative Properties of Sleep Activates natural sleep pathwaysActivates natural sleep pathways Increased rate of healingIncreased rate of healing –Promotes anabolism Facilitates growth hormone releaseFacilitates growth hormone release –Counteracts catabolism Inhibits cortisol releaseInhibits cortisol release Inhibits catecholamine releaseInhibits catecholamine release

11 Harmful Effects of Sleep Deprivation  pressor response to sympathetic stimulation  pressor response to sympathetic stimulation Impaired CV response to positioning changeImpaired CV response to positioning change  BP, HR + urine norepinephrine  BP, HR + urine norepinephrine Immune dysfunctionImmune dysfunction –  ability of lymphocytes to synthesize DNA –  leukocyte phagocytic activity –  interferon production by lymphocytes Cognitive dysfunctionCognitive dysfunction –Impaired memory, communication skills –Impaired decision-making –Confusional state [ICU]: apathy, delirium

12 Mechanisms for Analgesic Effect Disinhibit A5/A7 noradrenergic pathways Activate PAG; activate noradrenergic pathways Descending inhibitory pathways Decrease emotive aspects Subcortical + cortex Inhibit firing Second order neurons Inhibit release of SP and glutamate Primary afferent neurons Inhibit sympathetic- mediated pain  inflammation [e.g., bradykinin, other kinins ] Peripheral nociceptors  2 Agonists Opioids

13 Dex: Package Insert Info IndicationsIndications –Sedation of intubated and ventilated patients during treatment in an ICU setting x 24 h ContraindicationsContraindications –Caution in patients with advanced heart block, severe ventricular dysfunction, shock Drug interactionsDrug interactions –Vagal effects can be counteracted by atropine / glyco Clearance is lower w hepatic impairmentClearance is lower w hepatic impairment Withdrawal sx after discontinuation: not seen after 24 h useWithdrawal sx after discontinuation: not seen after 24 h use Adrenal insufficiency: no effect on cortisol response to ACTHAdrenal insufficiency: no effect on cortisol response to ACTH

14 Clinical Uses of Dex in Anesthesia Bariatric surgeryBariatric surgery Sleep apnea patientsSleep apnea patients Craniotomy: aneurysm, AVM [hypothermia]Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgeryCervical spine surgery Off-pump CABGOff-pump CABG Vascular surgeryVascular surgery Thoracic surgeryThoracic surgery Conventional CABG Back surgery, evoked potentials Head injury Burn Trauma Alcohol withdrawal Awake intubation

15 Ogan OU, Plevak DJ: Mayo Clinic; Sleep Apnea Patients Anesthesia considerations Morbid obesity, at risk for aspirationMorbid obesity, at risk for aspiration Difficult IV accessDifficult IV access Systemic + pulm HTN, cor pulmonaleSystemic + pulm HTN, cor pulmonale Postop airway obstruction + ventilatory arrest with anesthetic drugsPostop airway obstruction + ventilatory arrest with anesthetic drugs –  upper airway muscle activity –inhibition of normal arousal patterns –upper airway swelling from laryngoscopy, surgery, intubation Dexmedetomodine Anesthetic adjunct to minimize opioid + sedative useAnesthetic adjunct to minimize opioid + sedative use

16 Craig MG et al: IARS abstract, Baylor Gastric Bypass Surgery Patients Morbidly obese patients Prone to hypoxemiaProne to hypoxemia Sleep apnea is commonSleep apnea is common Respiratory depression w opioidsRespiratory depression w opioids Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, prospectively studied in 32 pts  opioid use in dex group  opioid use in dex group 1 pt in control gp needed reintubation1 pt in control gp needed reintubation Dex pts more likely to be normotensive w  HRDex pts more likely to be normotensive w  HR

17 Ramsay MA, et al: Anesthesiology, 2002: A-910 and A-165. Baylor Dex Improves Postop Pain Mgt after Bariatric Surgery RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr prior to end of surgery [vs.saline]. Double- blind Infusion adjusted according to needInfusion adjusted according to need Dex continued in PACUDex continued in PACU PACU pain control with PCAPACU pain control with PCADexmedetomidine Morphine use  in dex gp (P < 0.03)Morphine use  in dex gp (P < 0.03) Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01)Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01) % time pain free in PACU  in dex gp:% time pain free in PACU  in dex gp: –44% vs 0 (P < 0.002) Better control of HR in dex gpBetter control of HR in dex gp

18 Doufas AG et al: Stroke 2003;34. Louisville, KY Craniotomy for Aneurysm / AVM Anesthesia considerations Smooth induction + emergenceSmooth induction + emergence Prevent rupturePrevent rupture Avoid cerebral ischemiaAvoid cerebral ischemia Hypothermia (33 o C)  CMRO 2, CBF, CBV, CSF, ICPHypothermia (33 o C)  CMRO 2, CBF, CBV, CSF, ICPDexmedetomodine  sympathetic stimulation  sympathetic stimulation  or no change in ICP  or no change in ICP  shivering w/o resp depression  shivering w/o resp depression Preserved cognitive fctPreserved cognitive fct –reliable serial neuro exams

19 Herr DL: Crit Care Med 2000;28:M248. Washington Hospital Coronary Artery Surgery Patients Herr study, n=300: Dex vs. controls [propofol] RCT, dex started at sternal closure, 0.4 ug/kg/hr after loading dose, and 0.2 to 0.7 ug/kg/hr for hrs after extubationRCT, dex started at sternal closure, 0.4 ug/kg/hr after loading dose, and 0.2 to 0.7 ug/kg/hr for hrs after extubation Ramsay > 3 before extub, Ramsay 2 after extubRamsay > 3 before extub, Ramsay 2 after extubDexmedetomidine Faster time to extub in dex gpFaster time to extub in dex gp –by 1 hr 94% did not require propofol94% did not require propofol 70% did not require morphine70% did not require morphine –(vs. 34% controls) Dex pts had less Afib (7 vs 12 pts)Dex pts had less Afib (7 vs 12 pts)

20 Sumping ST: CCM 2000;28:M249. Duke CABG and Lung Disease Lung Disease Often delays tracheal extubationOften delays tracheal extubation RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug/kg/hr, + continued 6 hr after extubation vs. controls (propofol)RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug/kg/hr, + continued 6 hr after extubation vs. controls (propofol) Ramsay > 3 before extub, Ramsay 2 after extubRamsay > 3 before extub, Ramsay 2 after extubDexmedetomidine Faster time to extub:Faster time to extub: – h v h No difference in PaCO2 between gps 30 min after extub: 37.9 v mmHgNo difference in PaCO2 between gps 30 min after extub: 37.9 v mmHg

21 Thoracotomy + Thoracoscopy Thoracotomy + thoracoscopy patients COPD, pleural effusion, marginal pulmonary fctCOPD, pleural effusion, marginal pulmonary fct  pCO 2 +  pO 2 with opioids for analgesia  pCO 2 +  pO 2 with opioids for analgesia Thoracic epidural: mainly for thoracotomyThoracic epidural: mainly for thoracotomy Dex: mainly for thoracoscopyDex: mainly for thoracoscopyDexmedetomidine Patients are arousable, but sedatedPatients are arousable, but sedated Does not  ventilatory driveDoes not  ventilatory drive Greatly  need for opioidsGreatly  need for opioids Alternative to thoracic epiduralAlternative to thoracic epidural Continue after extubationContinue after extubation

22 Talke et al: Anesth Analg 2000;90:834. Multicenter Vascular Surgery Vascular surgery patients Usually at risk for CAD, ischemia, HTN, tachycardiaUsually at risk for CAD, ischemia, HTN, tachycardia Dex attenuates periop stress responseDex attenuates periop stress response Dex attenuates  BP w AXC, especially thoracic aortaDex attenuates  BP w AXC, especially thoracic aortaDexmedetomidine RCT, n=41. Dex continued 48 hr postopRCT, n=41. Dex continued 48 hr postop HR  in dex gp at emergenceHR  in dex gp at emergence – v bpm Better control of HR in dex gpBetter control of HR in dex gp Plasma NE levels  in dex gpPlasma NE levels  in dex gp

23 Wijeysundera, Am J Med 2003;114:742. Univ of Toronto Meta- Analysis of Alpha-2 Agonists 23 trials, n=3395. All surgeries:  mortality + ischemiaAll surgeries:  mortality + ischemia Vascular:  MI + mortalityVascular:  MI + mortality Cardiac:  ischemiaCardiac:  ischemia Cardiac:  BP (more hypotension)Cardiac:  BP (more hypotension)Conclusions: Not class 1 evidence yet, but trials look promisingNot class 1 evidence yet, but trials look promising –Especially vascular surgery

24 Other Surgical Procedures Neck + back surgeryNeck + back surgery –Dex causes minimal effect on SSEP monitoring –Smooth emergence, especially cervical spine –Easy to evalute neuro fct prior to + after extub Abdominal surgeryAbdominal surgery –Dexmedetomidine provides analgesia without respiratory depression –Especially useful in elderly undergoing colon resections, TAH, + other stressful procedures

25 Perioperative Dex Infusion Protocol Example: 70 kg patient. Assess BP, HR, volume status 2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml Hypovolemic Start at 40 mL/hr Stop load if  HR Usual load: 25 to 35 ug or 6 to 9 mL over min Monitor BP/HR throughout If bradycardia,  infusion Monitor BP/HR throughout If bradycardia,  infusion Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr] Volume preload 500 to 1000 cc LR Normovolemic Dex=dexmedetomidine.

26 Considerations With Anesthesia Use of Dexmedetomidine Dilute in 0.9% saline: 4 mcg/mLDilute in 0.9% saline: 4 mcg/mL Requires infusion pump: mcg/kg/hRequires infusion pump: mcg/kg/h Transient HTN: with rapid bolusTransient HTN: with rapid bolus Hypotension may occur, especially if hypovolemiaHypotension may occur, especially if hypovolemia  HR (attenuation of tachycardia): usually desirable  HR (attenuation of tachycardia): usually desirable  conc of inhaled agents: BIS monitoring  conc of inhaled agents: BIS monitoring Continue infusion after extubation for 30 min [PACU]Continue infusion after extubation for 30 min [PACU] L + D: not studiedL + D: not studied Pediatrics: abstracts + case reports [Lerman, Toronto]Pediatrics: abstracts + case reports [Lerman, Toronto] Geriatrics: more hypotension + bradycardia:  doseGeriatrics: more hypotension + bradycardia:  dose

27 Use of Dexmedetomidine in the Burn Unit  2 agonist effect assists in the management of burn patients; blunts catecholamine surge  2 agonist effect assists in the management of burn patients; blunts catecholamine surge Use in intubated and non-intubated burn patientsUse in intubated and non-intubated burn patients Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr)Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr)  dose for less severe burns and non-intubated patients  dose for less severe burns and non-intubated patients –0.2 to 0.4 mcg/kg/hr for routine burn care –outpatient dressing changes, instead of ketamine

28 Alcohol Withdrawal and Trauma Trauma often occurs in males who are intoxicatedTrauma often occurs in males who are intoxicated Trauma pt may experience agitation and is at risk for exacerbating underlying injuries (e.g., SCI)Trauma pt may experience agitation and is at risk for exacerbating underlying injuries (e.g., SCI) Benzodiazepines typically usedBenzodiazepines typically used –Intubation and ventilation often required if extreme agitation Dexmedetomidine is an alternativeDexmedetomidine is an alternative –Spontaneous breathing –Hemodynamic stability –Adequate sedation –Prevention of autonomic effects of withdrawal –Pain control

29 Summary Goal is to establish + maintain adequate drug conc at effector site to produce desired effectGoal is to establish + maintain adequate drug conc at effector site to produce desired effect Dex can help optimize anesthesia via:Dex can help optimize anesthesia via: –Sedation, analgesia +  sympathetic activity –Attenuation of stress response +  HR –Smooth emergence + tracheal extubation Unique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depressionUnique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depression Adjunct agent of choice for many surgeriesAdjunct agent of choice for many surgeries


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